P450: PRECLINICAL AND CLINICAL SIGNS OF RVU120 EFFICACY, A SPECIFIC CDK8/19 INHIBITOR IN DNMT3A MUTATION POSITIVE AML AND HR-MDS
Authors: U. Pakulska, N. Angelosanto, M. Mikula, H. Nogai, R. Dudziak, C. Abboud, M. Obacz, K. Goller, M. Cybulska, M. Mazan, M. Kozakowska, T. Rzymski
Journal: HemaSphere (2022)

Background: CDK8 and its paralog CDK19 regulate transcription as a part of mediator complex, that links enhancers with core promoters. AML likewise many other cancers highjack CDK8 and CDK19 to maintain undifferentiated state and prevent apoptotic cell death. First CDK8/CDK19 inhibitor RVU120 has reached clinical development phase Ib (NCT04021368) in AML and HR-MDS patients. Aims: It is now critical to establish relationship between preclinical and clinical efficacy results, and molecular characteristics in order to identify actionable markers predicting response to CDK8/CDK19 inhibitors. Methods: Association of molecular profiles with responses to RVU120 has been performed on genetically annotated AML PDCs, followed by flow cytometry and bioinformatic analysis. PDCs were implanted intravenously into NSG-SGM3 mice and after disease onset animals were treated orally with RVU120. Profiling of transcriptional response to RVU120 in DMNT3A mutant cells has been performed by RNA-seq. The First in Human study of RVU120 is currently active enrolling R/R AML or HR-MDS patients, in a dose escalation design aimed at exploring safety/tolerability and identify the RPD2. RVU120 is administered orally, each other day for 7 total doses per 21 days cycle, until disease progression/unacceptable toxicity. Response to the study drug is assessed according to Dohner 2017 criteria. Results: Screening of AML PDC against RVU120 indicated high anti-cancer efficacy in >40% of tested samples. Correlation of efficacy with genetic profile of samples indicated specific enrichment of DNMT3A or NPM1 mutants in responder group. These results were further corroborated in disseminated PDX AML model, showing complete clearance of DNMT3A and NPM1 mutation- positive blasts and recovery of murine BM in animals treated with RVU120. Transcriptomic analysis of DNMT3A and NPM1 positive AML cells indicated distinct transcriptomic profiles, characterized by high expression of homeobox genes, involved in determination of cell faith. Immunophenotyping of responder cells indicated elimination of lineage committed blast cells. At the date of this abstract submission, 13 patients have been enrolled into CLI120-001 trial, including 2 patients with DNMT3A mutations. Notably, first R/R AML patient that achieved CR was positive for DNMT3A and NPM1 mutations. At study entry this patient was progressing with pancytopenia, 65% BM blasts and extramedullary localization of leukemia. BM showed a complete clearance of blasts at the end of 1st cycle of 75mg dose, followed by hematological recovery and signs of monocytic differentiation. Importantly, monocytic differentiation is observed as a pharmacodynamic effect of RVU120 in preclinical studies. Skin leukemia lesions improved gradually up to a CR in cycle 7. Second DNMT3A mutation patient with HR-MDS, escalated from 50 to 75 mg dose from cycle 7, continues treatment at the cycle 24 with SD and erythroid hematological improvement. Summary/Conclusion: AML PDCs with DNMT3and NPM1 mutations show differential sensitivity to RVU120 treatment both in vitro and in vivo. Anti-cancer efficacy of RVU120 was associated with transcriptomic reprogramming and lineage commitment. Preliminary evidence of clinical response to RVU120 has been also shown in R/R AML and HR-MDS patients positive for DNMT3A mutations. Further molecular studies in greater number of patients under RVU120 treatment are ongoing and will provide evidence for predictive markers of response to RVU120 in AML.